Analgesic combination of oxycodone and T-614

ABSTRACT

Disclosed is a pharmaceutical composition, comprising a combination of a dose of T-614 or a pharmaceutically acceptable salt thereof and a dose of oxycodone or a pharmaceutically acceptable salt thereof, said combination in an amount sufficient to provide an analgesic effect in a human patient. Also disclosed is a method of effectively treating pain in humans or other mammals, comprising administering to the patient a combination of a dose of T-614 or a pharmaceutically acceptable salt thereof and a dose of oxycodone or a pharmaceutically acceptable salt thereof such that the dosing interval of the T-614 overlaps with the dosing interval of the oxycodone, said combination in an amount sufficient to provide an analgesic effect in a human patient.

FIELD OF THE INVENTION

[0001] The invention relates to analgesic pharmaceutical compositionscontaining an opioid analgesic and a cyclooxygenase-2 (COX-2) inhibitor.The invention also relates to methods of treating pain comprisingadministering such pharmaceutical compositions to human patients.

BACKGROUND OF THE INVENTION

[0002] There is a continuing need for analgesic medications able toprovide high efficacy pain relief while reducing the possibility ofundesirable effects. Non-steroidal anti-inflammatory drugs (“NSAID'S”),including compounds such as ibuprofen, ketoprofen and diclofenac, haveanti-inflammatory actions and are effective on pain associated with therelease of prostaglandins and other mediators of inflammation. Forexample, diclofenac is considered to be extremely potent and effectiveas an analgesic and anti-inflammatory agent. Diclofenac is approved inthe United States for the long-term symptomatic treatment of rheumatoidarthritis, osteoarthritis and ankylosing spondylitis. It is alsoconsidered to be useful for the short-term treatment of acutemusculoskeletal injury, acute painful shoulder, postoperative pain anddysmenorrhea. However, NSAID'S such as diclofenac produce side effectsin about 20% of patients that require cessation of medication. Sideeffects include, for example, gastrointestinal bleeding and the abnormalelevation of liver enzymes.

[0003] The opioids are a group of drugs, both natural and synthetic,that are employed primarily as centrally-acting analgesics and are opiumor morphine-like in their properties (Gilman et al., 1980, GOODMAN ANDGILMAN'S, THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 24:494-534,Pub. Pergamon Press; hereby incorporated by reference). The opioidsinclude morphine and morphine-like homologs, including, e.g., thesemisynthetic derivatives codeine (methylmorphine) and hydrocodone(dihydrocodeinone) among many other such derivatives. Morphine andrelated opioids exhibit agonist activity at central nervous system orCNS (referring to the brain and spinal cord) μ (mu) opioid receptors aswell as showing affinity for the δ and κ opioid receptors, to produce arange of effects including analgesia, drowsiness, changes in mood andmental clouding. In addition to potent analgesic effects, themorphine-related opioids may also cause a number of undesirable effects,including, for example, respiratory depression, nausea, vomiting,dizziness, mental clouding, dysphoria, pruritus, constipation, increasedbiliary tract pressure, urinary retention and hypotension. Thedevelopment of tolerance to the opioid drugs and the risk of chemicaldependence and abuse for these drugs is another undesirable effect.

[0004] Morphine, which has been considered the prototypic opioidanalgesic, has been available in many dosage forms, including immediaterelease oral dosage forms, and more recently, formulated into 12 hourcontrolled release formulations (e.g., MS Contin® tablets, commerciallyavailable from Purdue Frederick Company). Other opioid analgesics havebeen available as immediate release oral dosage forms, such ashydromorphone (e.g., Dilaudid®, commercially available from KnollPharmaceuticals). More recently, another controlled release opioidanalgesic, oxycodone, has become available (OxyContin®, commerciallyavailable from Purdue Pharma). There are, of course, many other oralformulations of immediate release and sustained release opioids whichare commercially available throughout the world.

[0005] Prior publications report that analgesic potency may be improvedwhile reducing undesirable effects by combining an opioid with an NSAIDor an analgesic such as acetylsalicylic acid or acetaminophen, in such away as to obtain a synergistic analgesic effect allowing for a reductionin the total dose of both the NSAID and analgesic. For example, U.S.Pat. No. 4,569,937, issued to Baker et al. on Feb. 11, 1986, describes acombination of oxycodone with ibuprofen in a ratio ofoxycodone/ibuprofen from 1:6 to about 1:400. U.S. Pat. No. 4,690,927,issued to Voss et al. on Sep. 1, 1987, describes a combination of theNSAID diclofenac and codeine in a weight ratio of diclofenac to codeineof about 1:1 to about 3:1. U.S. Pat. No. 5,190,947, issued to Riess etal. on Mar. 2, 1993, describes a diclofenac-codeine salt([2-[2,6-dichlorophenyl)-amino]-phenyl]-acetic acid). U.S. Pat. No.4,844,907, issued to Elger et al. on Jul. 4, 1989, describes amultiphase tablet combining a narcotic analgesic phase and an NSAIDphase in separate layers. U.S. Pat. No. 4,587,252, issued to Arnold etal. on May 6, 1986, describes a process for treating pain using acombination of hydrocodone and ibuprofen.

[0006] Non-steroidal, anti-inflammatory drugs (NSAID'S) exert most oftheir anti-inflammatory, analgesic and antipyretic activity and inhibithormone-induced uterine contractions and certain types of cancer growththrough inhibition of prostaglandin G/H synthase, also known ascyclooxygenase.

[0007] Fatty acid cyclooxygenase (COX) was described as the source ofprostaglandins, thromboxanes, and a variety of other arachidonic acid-,and higher desaturated fatty acid-derived biologically activehydroxylated metabolites. Beginning in the late 1960's, B. Sammuelsson,S. Bergstrom and their colleagues discovered the biological activity andelucidated the structures of the products of cyclooxygenase. In the late1960's and early 1970's, J. Vane discovered that aspirin and otherNSAIDs exert their major biological activities by inhibitingcyclooxygenase. COX is directly responsible for the formation of PGG andPGH and these serve as the intermediates in the synthesis of PGD, PGE,PGF, PGI, and TXA. By the late 1970's and early 1980's, it wasappreciated that many hormones and other biologically active agentscould regulate the cellular activity of COX. At first, it was assumedthat COX induction was the simple result of oxidative inactivation ofCOX,which happens after only a few substrate turnovers. This is commonamong enzymes that incorporate molecular oxygen into theirsubstrates—the oxygen rapidly degrades the enzyme. Such enzymes aresometimes referred to as suicide enzymes. In response to the rapid(within seconds) inactivation of cyclooxygenase, its message istranscribed, and the enzyme is rapidly induced to replace that lost dueto catalysis. It was noticed by several groups that cyclooxygenase wasinduced to a much greated degree than necessary to replace the lostenzyme. Using an oligonucleotide directed to the cloned COX-1 enzyme, asecond band was identified on Northern blots under low stringency. Thisgene was cloned and identified as a second COX enzyme, named COX-2, andwas found to be largely absent from many cells under basal conditionsbut rapidly induced by several cytokines and neurotransmitters. Theexpression of this enzyme was found to be largely responsible for thepreviously-observed excess COX activity in activated cells. The genesfor COX-1 and COX-2 are distinct, with the gene for COX -1 being 22 kband the message size 2.8 kb whereas the gene for COX-2 is 8.3 kb and themessage size 4.1 kb. Whereas the COX-1 promoter does not containrecognized transcription factor binding sites, the COX-2 promotercontains sites for NF-κB, AP-2, NF-IL-6 and glucocorticoids (H. R.Herschman, Cane. Metas. Rev. 13:256, 1994). There are some differencesin the active sites of the enzymes. Aspirin inhibits the cyclooxygenaseactivity of COX-1 but leaves intact its peroxidase activity, whereasaspirin converts COX-2 from a cyclooxygenase to a 15-lipoxygenase (E. A.Meade et al, J. Biol. Chem. 268:6610, 1993).

[0008] It has been proposed that the COX-1 is responsible, in many cellsfor endogenous basal release of prostaglandins and is important in thephysiological functions of prostaglandins which include the maintenanceof gastrointestinal integrity and renal blood flow. Inhibition of COX-1causes a number of side effects including inhibition of plateletaggregation associated with disorders of coagulation, andgastrointestinal toxicity with the possibility of ulcerations and ofhemorrhage. It is believed that the gastrointestinal toxicity is due toa decrease in the biosynthesis of prostaglandins which arecytoprotective of the gastric mucosa.

[0009] A high incidence of side effects has historically been associatedwith chronic use of classic cyclooxygenase inhibitors, all of which areabout equipotent for COX-1 or COX-2, or which are COX-1-selective. Whilerenal toxicity occurs, it usually becomes evident in patients who arealready exhibit renal insufficiency (D. Kleinknecht, Sem. Nephrol.15:228, 1995). By far, the most prevalent and morbid toxicity isgastrointestinal. Even with relatively nontoxic drugs such as piroxicam,up to 4% of patients experience gross bleeding and ulcertaion (M. J. S.Langman et al, Lancet 343:1075, 1994). In the United States, it isestimated that some 2000 patients with rheumatoid arthritis and 20,000patients with osteoarthritis die each year due to gastrointestinal sideeffects related to the use of COX inhibitors. In the UK, about 30% ofthe annual 4000 peptic ulcer-related deaths are attributable to COXinhibitors (Scrip 2162,p.17). COX inhibitors cause gastrointestinal andrenal toxicity due to the inhibition of synthesis of homeostaticprostaglandins responsible for epithelial mucus production and renalblood flow, respectively.

[0010] The second form of cyclooxygenase, COX-2, is rapidly and readilyinducible by a number of agents including mitogens, endotoxins,hormones, cytokines and growth factors.

[0011] It has been proposed that COX-2 is mainly responsible for thepathological effects of prostaglandins, which arise when rapid inductionof COX-2 occurs in response to such agents as inflammatory agents,hormones, growth factors, and cytokines. A selective inhibitor of COX-2therefore would have anti-inflammatory, antipyretic and analgesicproperties similar to those of a conventional non-steroidalanti-inflammatory drug (NSAID). Additionally, a COX-2 inhibitor wouldinhibit hormone-induced uterine contractions and have potentialanti-cancer effects. A COX-2 inhibitor would have advantages overNSAID'S such as a diminished ability to induce some of themechanism-based side effects. Moreover, it is believed that COX-2inhibitors have a reduced potential for gastrointestinal toxicity, areduced potential for renal side effects, a reduced effect on bleedingtimes and a lessened ability to induce asthma attacks inaspirin-sensitive asthmatic subjects.

[0012] Thus, compounds with high specificity for COX-2 over COX-1, maybe useful as alternatives to conventional NSAID'S. This is particularlythe case when NSAID use is contra-indicated, such as in patients withpeptic ulcers, gastritis, regional enteritis, ulcerative colitis,diverticulitis or with a recurrent history of gastrointestinal lesions;GI bleeding, coagulation disorders including anemia,hypoprothrombinemia, haemophelia or other bleeding problems; kidneydisease, and patients about to undergo surgery or taking anticoagulants.

[0013] Once it became clear that COX-1 but not COX-2 is responsible forgastrointestinal epithelial prostaglandin production and a majorcontributor to renal prostaglandin synthesis, the search for selectiveCOX-2 inhibitors became extremely active. This led very quickly to therecognition that several COX inhibitors, including nimesulide andDup-697, which were known to cause little or no gastrointestinalirritation, are COX-2-selective.

[0014] U.S. Pat. No. 5,409,944 (Black, et al.) describes certain novelalkane-sulfonamido-indanone derivatives useful for the treatment ofpain, fever, inflammation, arthritis, cancer, and other disease states.Also discussed therein are compositions for the treatment ofcyclooxygenase-2-mediated diseases comprising the therein-describednovel alkane-sulfonamidoindanone derivatives together with a painreliever including acetaminophen or phenacetin; a potentiator includingcaffeine; an H2-antagonist, aluminium or magnesium hydroxide,simethicone, a decongestant including phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, epinephrine,naphazoline, xylonetazoline, propylhexedrine, or levo-desoxy ephedrine;an antitussive including codeine, hydrocodone, caramiphen,carbetapentane or dextromethorphan; a diuretic and/or a sedating ornon-sedating antihistamine. While Black et al. mention the use of anantitussive dose of two opioid analgesics (codeine and hydrocodone),they do not describe or suggest the use of their COX-2 inhibitors withanalgesically effective amounts of any opioid analgesics.

SUMMARY OF THE INVENTION

[0015] It is an object of the present invention to provide a method andpharmaceutical formulation (medicament) which allows for reduced plasmaconcentrations of an opioid analgesic, while still providing effectivepain management.

[0016] It is a futher object of the present invention to provide amethod and pharmaceutical formulation (medicament) for effectivelytreating patients in pain with an opioid analgesic which achievesprolonged and effective pain management, while at the same time providesthe opportunity to reduce side effects, dependence and tolerance whichthe patients may experience when subjected to prolonged treatment withan opioid.

[0017] It is yet a further object to provide a method and pharmaceuticalformulation (medicament) for the effective treatment of pain in patientsby augmenting the analgesic effect of a COX-2 inhibitor.

[0018] The invention is directed to the surprising synergy obtained viathe administration of an opioid analgesic together with a COX-2inhibitor.

[0019] The present invention is related in part to analgesicpharmaceutical compositions comprising a COX-2 inhibitor together withan opioid analgesic. The opioid analgesic and COX-2 inhibitor can beadministered orally, via implant, parenterally, sublingually, rectally,topically, via inhalation, etc. In other embodiments of the invention,the COX-2 inhibitor can be administered separately from the opioidanalgesic, as set forth in more detail below.

[0020] The invention allows for the use of lower doses of the opioidanalgesic or the COX-2 inhibitor (referred to as “apparent one-waysynergy” herein), or lower doses of both drugs (referred to as “two-waysynergy” herein) than would normally be required when either drug isused alone. By using lower amounts of either or both drugs, the sideeffects associated with effective pain management in humans aresignificantly reduced.

[0021] In certain preferred embodiments, the invention is directed inpart to synergistic combinations of a COX-2 inhibitor in an amountsufficient to render a therapeutic effect together with an opioidanalgesic, such that an an analgesic effect is attained which is atleast about 5 (and preferably at least about 10) times greater than thatobtained with the dose of opioid analgesic alone, except forcombinations of the Cox-2 inhibitor with anti-tussive doses ofhydrocodone or codeine. In certain embodiments, the synergisticcombination provides an analgesic effect which is up to about 30-40times greater than that obtained with the dose of opioid analgesicalone. In such embodiments, the synergistic combinations display what isreferred to herein as an “apparent one-way synergy”, meaning that thedose of COX-2 inhibitor synergistically potentiates the effect of theopioid analgesic, but the dose of opioid analgesic does not appear tosignificantly potentiate the effect of the COX-2 inhibitor. In certainembodiments, the combination is administered in a single dosage form. Inother embodiments, the combination is administered separately,preferably concomitantly. In certain preferred embodiments, thesynergism exhibited between the COX-2 inhibitor and the opioid analgesicis such that the dosage of opioid analgesic would be sub-therapeutic ifadministered without the dosage of COX-2 inhibitor. In other preferredembodiments, the present invention relates to a pharmaceuticalcomposition comprising an analgesically effective dose of an opioidanalgesic together with a dose of a COX-2 inhibitor effective to augmentthe analgesic effect of the opioid analgesic.

[0022] Although certain embodiments of the invention are directed tosynergistic combinations of a COX-2 inhibitor together with an opioidanalgesic, where there is an apparent “one-way synergism”, it isbelieved that in actuality these combinations exhibit two-way synergism,meaning that the COX-2 inhibitor potentiates the effect of the opioidanalgesic, and the opioid analgesic potentiates the effect of the COX-2inhibitor. Thus, other embodiments of the invention relate tocombinations of a COX-2 inhibitor and an opioid analgesic where the doseof each drug is reduced due to the synergism demonstrated between thedrugs, and the analgesia derived from the combination of drugs inreduced doses is surprisingly enhanced. The two-way synergism is notalways readily apparent in actual dosages due to the potency ratio ofthe opioid analgesic to the COX-2 inhibitor (meaning that the opioidgenerally displays much greater relative analgesic potency).

[0023] In certain preferred embodiments, the invention is directed topharmaceutical formulations comprising a COX-2 inhibitor in an amountsufficient to render a therapeutic effect together with atherapeutically effective or sub-therapeutic amount of an opioidanalgesic selected from the group consisting of alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, cyclazocine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levallorphan, levorphanol, levophen-acylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone,nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol,salts thereof, complexes thereof; mixtures of any of the foregoing,mixed mu-agonists/antagonists, mu-antagonist combinations, salts orcomplexes thereof, and the like. In certain preferred embodiments, theopioid analgesic is a mu or kappa opioid agonist. In certain preferredembodiments, the invention is directed to pharmaceutical formulationscomprising a COX-2 inhibitor in an amount sufficient to render atherapeutic effect together with a therapeutically effective orsub-therapeutic amount of an opioid analgesic selected from the groupconsisting of morphine, dihydrocodeine, hydromorphone, oxycodone,oxymorphone, salts thereof, and mixtures of any of the foregoing.

[0024] In certain preferred embodiments, the invention is directed topharmaceutical formulations comprising a COX-2 inhibitor in an amountsufficient to render a therapeutic effect together with a dose ofcodeine which is analgetic if administered without the COX-2 inhibitor.Such a dose of codeine is preferably from about 30 to about 400 mg.

[0025] In certain preferred embodiments, the invention is directed topharmaceutical formulations comprising a COX-2 inhibitor in an amountsufficient to render a therapeutic effect together with a dose ofhydrocodone which is analgetic if administered without the COX-2inhibitor. Such a dose of hydrocodone is preferably from about 5 toabout 2000 mg, and preferably at least about 15 mg hydrocodone.

[0026] The invention further relates to a method of effectively treatingpain in humans, comprising administering to a human patient atherapeutically effective amount of a COX-2 inhibitor together with adose of an opioid analgesic, such that the combination provides ananalgesic effect which is at least about 5 (and preferably at leastabout 10) times greater than that obtained with the dose of opioidanalgesic alone. In certain embodiments, the synergistic combinationprovides an analgesic effect which is up to about 30-40 times greaterthan that obtained with the dose of opioid analgesic alone. In certainpreferred embodiments, the doses of the COX-2 inhibitor and the opioidanalgesic are administered orally. In further preferred embodiments, thedoses of the COX-2 inhibitor and the opioid analgesic are administeredin a single oral dosage form. In certain preferred embodiments, the doseof opioid analgesic would be sub-therapeutic if administered without thedose of COX-2 inhibitor. In other preferred embodiments, the dose ofopioid analgesic is effective to provide analgesia alone, but the doseof opioid provides at least a five-fold greater analgesic effect thantypically obtained with that dose of opioid alone.

[0027] The invention further relates to the use of a pharmaceuticalcombination of a COX-2 inhibitor together with an opioid analgesic toprovide effective pain management in humans.

[0028] The invention further relates to the use of a COX-2 inhibitor inthe manufacture of a pharmaceutical preparation containing a COX-2inhibitor and an opioid analgesic for the treatment of pain.

[0029] The invention further relates to the use of an opioid analgesicin the manufacture of a pharmaceutical preparation containing a COX-2inhibitor and an opioid analgesic for the treatment of pain.

[0030] The invention is also directed to a method for providingeffective pain management in humans, comprising administering ananalgesically effective or sub-therapeutic amount of an opioidanalgesic; and administering an effective amount of a COX-2 inhibitor inan amount effective to augment the analgesic effect provided by saidopioid analgesic. The COX-2 inhibitor can be administered before,simultaneously with, or after administration of the opioid analgesic, aslong as the dosing interval of the COX-2 inhibitor overlaps with thedosing interval of the opioid analgesic (or its analgesic effects). Inother words, according to the method of the present invention, incertain preferred embodiments the COX-2 inhibitor need not beadministered in the same dosage form or even by the same route ofadministration as the opioid analgesic. Rather, the method is directedto the surprising synergistic and/or additive benefits obtained inhumans, when analgesically effective levels of an opioid analgesic havebeen administered to a human, and, prior to or during the dosageinterval for the opioid analgesic or while the human is experiencinganalgesia, an effective amount of COX-2 inhibitor to augment theanalgesic effect of the opioid analgesic is administered. If the COX-2is administered prior to the administration of the opioid analgesic, itis preferred that the dosage intervals for the two drugs overlap, i.e.,such that the analgesic effect over at least a portion of the dosageinterval of the opioid analgesic is at least partly attributable to theCOX-2 inhibitor.

[0031] In an additional method of the invention, the surprisingsynergistic and/or additive benefits obtained in humans are achievedwhen analgesically effective levels of a COX-2 inhibitor have beenadministered to a human, and, during the dosage interval for the COX-2inhibitor or while the human is experiencing analgesia by virtue of theadministration of a COX-2 inhibitor, an effective amount of an opioidanalgesic to augment the analgesic effect of the COX-2 inhibitor isadministered.

[0032] In a further embodiment of the present invention, the inventioncomprises an oral solid dosage form comprising an analgesicallyeffective amount of an opioid analgesic together with an amount of aCOX-2 inhibitor or pharmaceutically acceptable salt thereof whichaugments the effect of the opioid analgesic.

[0033] Optionally, the oral solid dosage form includes a sustainedrelease carrier which causes the sustained release of the opioidanalgesic, or both the opioid analgesic and the COX-2 inhibitor when thedosage form contacts gastrointestinal fluid. The sustained releasedosage form may comprise a plurality of substrates which include thedrugs. The substrates may comprise matrix spheroids or may compriseinert pharmaceutically acceptable beads which are coated with the drugs.The coated beads are then preferably overcoated with a sustained releasecoating comprising the sustained release carrier. The matrix spheroidmay include the sustained release carrier in the matrix itself; or thematrix may comprise a normal release matrix containing the drugs, thematrix having a coating applied thereon which comprises the sustainedrelease carrier. In yet other embodiments, the oral solid dosage formcomprises a tablet core containing the drugs within a normal releasematrix, with the tablet core being coated with a sustained releasecoating comprising the sustained release carrier. In yet furtherembodiments, the tablet contains the drugs within a sustained releasematrix comprising the sustained release carrier. In yet furtherembodiments, the tablet contains the opioid analgesic within a sustainedrelease matrix and the COX-2 inhibitor coated into the tablet as animmediate release layer.

[0034] In many preferred embodiments of the invention, thepharmaceutical compositions containing the COX-2 inhibitors and opioiddrugs set forth herein are administered orally. Such oral dosage formsmay contain one or both of the drugs in immediate or sustained releaseform. For ease of administration, it is preferred that the oral dosageform contains both drugs. The oral dosage forms may be in the form oftablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, multiparticulate formulations, syrups,elixirs, and the like.

[0035] The pharmaceutical compositions containing the COX-2 and/or theopioid drugs set forth herein may alternatively be in the form ofmicroparticles (e.g., microcapsules, microspheres and the like), whichmay be injected or implanted into a human patient, or other implantabledosage forms known to those skilled in the art of pharmaceuticalformulation. For ease of administration, it is preferred that suchdosage forms contain both drugs.

[0036] Additional pharmaceutical compositions comtemplated by theinvention further include transdermal dosage forms, suppositories,inhalation powders or sprays, and buccal tablets.

[0037] The combination of COX-2 inhibitor and opioid analgesic mayfurther be administered by different routes of administration.

[0038] It should be understood that for purposes of the presentinvention, the following terms have the following meanings:

[0039] The term “effective analgesia” is defined for purposes of thepresent invention as a satisfactory reduction in or elimination of pain,along with the process of a tolerable level of side effects, asdetermined by the human patient.

[0040] The term “effective pain management” means for purposes of thepresent invention as the objective evaluation of a human patient'sresponse (pain experienced versus side effects) to analgesic treatmentby a physician as well as subjective evaluation of therapeutic treatmentby the patient undergoing such treatment. The skilled artisan willunderstand that effective analgesia will vary according to many factors,including individual patient variations.

[0041] The term “opioid analgesic” is defined for purposes of thepresent invention as the drug in its base form, or a pharmaceuticallyacceptable salt or complex thereof.

[0042] The term “COX-2 inhibitor” is defined for purposes of the presentinvention as the drug in its base form, or a pharmaceutically acceptablesalt or complex thereof .

[0043] The term “sustained release” is defined for purposes of thepresent invention as the release of the drug (opioid analgesic) from thetransdermal formulation at such a rate that blood (e.g., plasma)concentrations (levels) are maintained within the therapeutic range(above the minimum effective analgesic concentration or “MEAC”) butbelow toxic levels over a period of time of about 12 hours or longer.

[0044] The term “steady state” means that the blood plasma concentrationcurve for a given drug has been substantially repeated from dose todose.

[0045] The term “minimum effective analgesic concentration” is definedfor purposes of this invention as the minimum effective therapeuticblood plasma level of the drug at which at least some pain relief isachieved in a given patient. It will be well understood by those skilledin the medical art that pain measurement is highly subjective and greatindividual variations may occur among patients.

DETAILED DESCRIPTION

[0046] The COX-2 inhibitors which are useful in the present inventionwill have similar anti-inflammatory, antipyretic and analgesicproperties as compared to conventional non-steroidal anti-inflammatorydrugs and in addition will inhibit hormone-induced uterine contractionsand have potential anti-cancer effects, but will have a diminishedability to induce some of the mechanism-based side effects. Inparticular, such COX-2 inhibitors should have a reduced potential forgastrointestinal toxicity, a reduced potential for renal side effects, areduced effect on bleeding times and a lessened ability to induce asthmaattacks in aspirin-sensitive asthmatic subjects. COX-2 inhibitors havebeen reported in the art and many chemical structures are known toproduce inhibition of cyclooxygenase-2. For purposes of the presentinvention, the term “COX-2 inhibitor” is defined as all compounds whichwould possess COX-2 inhibitory activity and which preferably have atleast 9-fold greater specificity for COX-2 over COX-1, either in-vitro(as determined, e.g., by IC50 measurements) or in-vivo (as determined,e.g., by ED50 measurements). Such COX-2 inhibitors will be useful inconjunction with the present invention and are considered to beencompassed by the appended claims. Preferably, the COX-2 inhibitorsused in the present invention demonstrate an in-vitro IC50 and/orin-vivo ED50 ratio for COX-1 to COX-2 of approximately 20-fold orgreater, more preferably 100-fold or greater, or most preferably incertain embodiments 1000-fold or greater.

[0047] Certain preferred COX-2 inhibitors include celecoxib (SC-58635),DUP-697, flosulide (CGP-28238), meloxicam, 6-methoxy-2 naphthylaceticacid (6-MNA), Vioxx (MK-966), nabumetone (prodrug for 6-MNA),nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.

[0048] There are a number of COX-2 inhibitors in development as ofmid-1998. These include meloxicam (commercially available in the U.K. asof 1996 from Boerhinger-Ingelheim); nimesulide (launched in 1985 inEurope from Hesinn); nabumetone (6-MNA is active metabolite)(commercially available as Relafin™ in the U.S.); celecoxib (SC-58635)(NDA filing by Searle estimated in September 1998); Vioxx (MK-966,L745337) (NDA filing by Merck estimated in November 1998); D-1367(Chiroscience; in Phase I in the U.K.); T-614 (Toyama; in Phase II inJapan and Phase I in the U.K.); and SC-57666 (Monsanto; in Phase I inthe U.S.).

[0049] In trials discussed at the 1996 annual meeting of the AmericanCollege of Rheumatology, celecoxib was demonstrated to be efficacious inpatients and devoid of gastrointestinal side effects in normalvolunteers (Scrip 2175, 25 October, 1996, p. 15). In studies in normalvolunteers, 128 subjects received celecoxib, 100 mg or 200 mg twice aday, or naproxen, or placebo, for one week. In the celecoxib groups andsubjects who received placebo, there were no gastrointestinal signs orsymptoms, whereas in the naproxen group, 20% of subjects experiencedgastrointestinal signs and symptoms. Further, in normal volunteers,celecoxib caused no alterations in platelet function. In a study inpatients, 293 patients, with osteoarthritis received celecoxib, 40 mg,100 mg, or 200 mg, or placebo twice a day for two weeks. Celecoxibreduced symptoms significantly, and drop-out rates in the higher dosecelcoxib groups were lower than for placebo. Patients with rheumatoidarthritis received celecoxib 100 mg, 200 mg, or 400 mg, or placebo,twicea day for four weeks. As in patients with osteoartliritis, symptomscores were improved in patients receiving celecoxib compared toplacebo, and drop-out rates were lower in patients taking celecoxib.COX-2 inhibitors have been reported in the art and many chemicalstructures are known to produce inhibition of cyclooxygenase-2.

[0050] COX-2 inhibitors are described in U.S. Pat. Nos. 5,616,601;5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,639,780;5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and 5,130,311,all of which are incorporated by reference. Many COX-2 inhibitors may bedescribed chemically as aryl sulfonamides. Indeed, both celecoxib andVioxx, which are considered to be “super-selective”, are arylsulfonamides, and more specifically, benzenesulfonamides. Thesecompounds will be useful in the methods and compositions of the presentinvention. However, one skilled in the art will appreciate that manyadditional COX-2 inhibitors have been identified in the art and would beuseful in conjunction with the methods and compositions of the presentinvention.

[0051] The use of structure-activity relationships in evaluating COXinhibitors is problematic because these COX inhibitors are suicideenzymes. Thus, when analyzed in an in-vitro assay, the IC50 value willchange over time. For this reason, published IC50's for common COXinhibitors have been reported as values varying by more than two ordersof magnitude from laboratory to laboratory. This makes it difficult tocompare the value for COX-1 inhibition obtained from one laboratory tothe value for COX-2 inhibition obtained from another laboratory. (See,for example D. E. Griswold and J. L. Adams, Med. Res. Rev. 16:181-206).Thus, it is preferable that when studying COX inhibitors to comparetheir relative potencies, comparisons only be made using results fromthe same assay, conducted at the same time. When using previouslygenerated data it is preferable to take data only from lists of severalcompounds that have been generated by one group so that the relativepotencies may be determined. Table 1 below provides representative datafor representative NSAIDs and certain COX-2 inhibitor compounds. Thedata have been collected from a number of different sources, and werechosen from available laboratories, using references which report onseveral compounds in the same paper, and which contain data that arerelatively compatible to data obtained from certain other laboratories(i.e., within a reasonable range of variation, with the understandingthat results from different laboraties can vary up to three orders ofmagnitude for agents that act as suicide enzymes). It should be kept inmind that most of the values reported in Table 1 are from in-vitroassays (except where potency is reported as mg/kg). The literatureconfirms that ratios of COX-1/COX-2 potency are generally kept in-vivo,but this is not always true. For example, indomethacin is alwaysCOX-1-selective in-vitro and in-vivo, but naproxen, which isCOX-1-selective in-vitro, is often (but not always) COX-2-selectivein-vivo. In part, this is due to the highly artificial in-vitro assayconditions used. The first two structural series were recognized as COXinhibitors that exhibited remarkably little ulcerogenic activity. Theseearly compounds included the aryl sulfonamides nimesulide, NS-398, andCGP 23238 and the 1,2-diarylheterocycles Dup-697 and SC-58125. Griswoldand Adams describe structure activity relationships in some detail (Med.Res. Rev. 16:282-206, 1996). TABLE 1 Selectivity of selectedcyclooxygenase inhibitors for COX-1 and Cox-2 COX-1 COX-2 COX-1/ DrugIC50, μM IC_(50, μM) COX-2 Ref Aspirin 1.67 278 0.004 l 32.4 mg/kg 198mg/kg 0.16 m Salicylate 254 725 0.36 l Ibuprofen 4.85 72.8 0.067 l 9.218.3 0.5 n Naproxen 4.8 28.4 0.17 a 0.6 2.0 0.3 b 6.6 3.9 1.7 c 15.6 280.56 n Diclofenac 0.04 0.1 0.4 d 2.7 20.5 0.13 a 1.5 1.05 1.4 c 0.0180.012 1.5 e Indomethacin 0.1 0.9 0.11 d 13.5 >1000 <0.013 a 0.00150.0089 0.15 e 2.35 mg/kg 0.67 mg/kg 3.3 m S-ketaprofen 0.11 0.18 0.61 nTenidap 0.39 47.8 0.008 f Piroxicam 17.7 >500 <0.035 a 1.07 mg/kg 0.76mg/kg 1.4 m Meloxicam 3.27 0.25 13 k 2.47 mg/kg 0.12 mg/kg 20 mNimesulide 70 1.27 55 b 9.2 0.52 17.7 n NS-398 >100 0.1 >1000 g 75 1.7742 b 16.8 0.1 168 N 6-MNA 64 94 0.7 A 240 35 7 H 278 187 1.5 I CGP 28238(fiosulide) 72.3 0.015 5000 E SC-58125 >100 0.09 >1100 j 38.7 0.27 143Celecoxib 15 0.04 375 o (SC-58635) Vioxx 369 1.5 246 n (L 745,337)Dup-697 0.8 0.01 80 d

[0052] For example, as reported by Famaey J P, Inflamm Res 1997November;46(11):437-446, nimesulide, a sulfonanilide compound withanti-inflammatory properties, possessed a pharmacological profilesuggesting that it might be a selective inhibitor of COX-2. In severalin vitro assays using either purified COX-2 and COX-1 preparations orcell preparations (both from animal and human origins) expressing COX-1or COX-2, ten out of eleven different groups demonstrated thatnimesulide selectively inhibits COX-2. The COX-2/COX-1 inhibitory ratiowas reported to vary, according to the assay preparation, from about0.76 to 0.0004 i.e. a 1.3 to 2,512-fold higher selectivity for COX-2than for COX-1. Further, an in-vivo whole blood assay performed onhealthy volunteers demonstrated a significant fall in COX-2 PGE2production without any effect on COX-1 TXB2 production (subjects treatedwith nimesulide 00 mg b.i.d. for 2 weeks) versus no effect on COX-2 PGE2and an almost total suppression of COX-1 TXB2 in subjects treated withaspirin (300 mg t.i.d. for 2 weeks). Nimesulide can thus be considered arelatively selective COX-2 inhibitor. At the recommended dosage of 100mg b.i.d., it is as effective an analgesic and anti-inflammatory agentas classical NSAIDs, and a well-tolerated drug with few side-effectsaccording to large-scale open studies and a global evaluation of a largenumber of controlled and non-controlled comparative trials.

[0053] A non-limiting list of opioid analgesic drugs which may beutilized in the present invention include alfentanil, allylprodine,alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine,butorphanol, clonitazene, codeine, cyclazocine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydro-codeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydrocodone, hydromorphone, hydroxy-pethidine, isomethadone,ketobemidone, levallorphan, levorphanol, levophenacyl-morphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, propheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, salts thereof, complexes thereof, mixtures of any of theforegoing, mixed mu-agonists/antagonists, mu-antagonist combinations,salts or complexes thereof, and the like. In certain preferredembodiments, the opioid analgesic is a mu or kappa opioid agonist. Inadditional preferred embodiments, the opioid analgesic is a selectivekappa agonist.

[0054] In certain preferred embodiments, the opioid analgesic isselected from codeine, hydromorphone, hydrocodone, oxycodone,dihydrocodeine, dihydromorphine, diamorpholne, morphine, tramadol,oxymorphone salts thereof, or mixtures thereof.

[0055] The present invention provides for analgesic preparations fororal administration that provide a combination of a COX-2 inhibitor or apharmaceutically acceptable salt thereof and an opioid analgesic or apharmaceutically acceptable salt thereof. The combination preferablyprovides a synergistic or at least additive effect for analgesicdosages.

[0056] Dosage levels of COX-2 inhibitor on the order of from about 0.005mg to about 140 mg per kilogram of body weight per day aretherapeutically effective in combination with an opioid analgesic.Alternatively, about 0.25 mg to about 7 g per patient per day of a COX-2inhibitor is administered in combination with an opioid analgesic. Forexample, inflammation may be effectively treated by the administrationof from about 0.005 to 50 mg of the COX-2 inhibitor per kilogram of bodyweight per day, or alternatively about 0.25 mg to about 3.5 g perpatient per day.

[0057] The amount of COX-2 inhibitor that may be combined with thecarrier materials to produce a single dosage form having COX-2 inhibitorand opioid analgesic in combination will vary depending upon the patientand the particular mode of administration. For example, a formulationintended for the oral administration of humans may contain from 0.25 mgto 5 g of COX-2 inhibitor compounded with an appropriate and convenientamount of carrier material which may vary from about 5 to about 95percent of the total composition. Unit dosages will generally containbetween from about 0.5 mg to about 1500 mg of a COX-2 inhibitor, andtypically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg,800 mg, or 1000 mg, etc., up to 1500 mg.

[0058] In one embodiment, the COX-2 inhibitor is provided in a sustainedrelease oral dosage form with hydromorphone as the therapeuticallyactive opioid in an amount from about 2 mg to about 64 mg hydromorphonehydrochloride. Alternatively, the dosage form may contain molarequivalent amounts of other hydromorphone salts or of the hydromorphonebase. In another embodiment, the opioid analgesic comprises morphine,and the sustained release oral dosage forms of the present inventioninclude from about 2.5 mg to about 800 mg morphine, by weight. In yetanother embodiment, the opioid analgesic comprises oxycodone and thesustained release oral dosage forms include from about 2.5 mg to about800 mg oxycodone. The opioid analgesic may comprise hydrocodone, and thesustained release oral dosage forms may include analgesic doses fromabout 8 mg to about 50 mg of hydrocodone per dosage unit. The opioidanalgesic may comprise tramadol and the sustained release oral dosageforms may include from about 25 mg to 800 mg tramadol per dosage unit.The dosage form may contain more than one opioid analgesic to provide asubstantially equivalent therapeutic effect.

[0059] Preferred combinations of the invention comprise an effectiveamount of a COX-2 inhibitor selected from the group consisting ofnimesulide, melorican, and flosulide, and an effective amount of anopioid analgesic selected from the group consisting of tramadol,hydromorphone, morphine, oxycodone, hydrocodone and dihydrocodeine inthe ratios set forth in Table I. In certain preferred embodiments, theratio of the afore-mentioned opioids to the afore-mentioned COX-2inhibitors is set forth in Table I. TABLE I Ratios of Opiates to COX-2Inhibitors COX-2 INHIBITORS OPIATES CELECOXIB FLOSULIDE MELOXICAMNABUMETONE NIMESULIDE T614 MK966 MORPHINE 0 001-1 0.001-1 0.05-500.0005-1 0.001-5 0 001-1 0.001-10 METHADONE 0.0001-1 0.0001-1 0 01-10 00001-1 0 001-1 0.0001-1 0 001-1 MEPERIDINE 0 01-100 0.001-1 0 001-500.004-1 0.01-1 0.01-10 1-100 LEVORHANOL 0.004-1 0.0001-1 0.001-10.00001-0.01 0.0002-1 0.0001-1 0.0001-1 HYDROMORPHONE 0.0003-3 0.0001-10 00001-1 0.0001-0.1 0.0001-1 0.0001-1 0.0001-1 OXYCODONE 0.001-100.0001-1 0.0001-1 0 0001-1 0 0001-1 0.0001-1 0.0001-1 HYDROCODONE0.001-10 0.0001-1 0.00011 0.0001-1 0.0001-1 0.0001-1 0.0001-1 CODEINE0.005-50 0.001-4 0.001-20 0.001-1 0.001-10 0.001-1 0.001-10

[0060] In other words, Table I describes test of ratios ofmorphine:celecoxib from about 0.001:1 to about 1:1; for methadone toflosulide the ratio is from about 0.0001:1 to about 1:1, and so on.

[0061] In certain preferred embodiments according to the presentinvention, an oral dosage form is preferred which includes the followingopioid/COX-2 inhibitor combinations: Morphine 40 mg plus 40 mgflosulide; morphine 40 mg plus 6 mg nimesulide; oxycondone 20 mg plus 20mg flosulide; oxycodone 40 mg plus 4 mg nimesulide; hydromorphone 5 mgplus 20 mg flosulide; or hydromorphone 5 mg plus 4 mg nimesulide.

[0062] The dosage administered will, of course, vary depending uponknown factors such as the pharmacodynamic characteristics of each agentof the combination and its mode and route of administration and upon theage, health and weight of the patient. The dosage will also depend uponthe nature and extent of symptoms, concurrent treatment, if any,frequency of treatment and the desired result. A composition comprisingany of the above-identified combinations of opioid analgesics and COX-2inhibitors may be administered in divided doses ranging from 2 to 6times per day or in a sustained release form that will provide a rate ofrelease effective to attain the desired results.

[0063] The optimal COX-2 inhibitor and opioid analgesic ratios aredetermined by standard assays well known in the art for determiningopioid and analgesic activity. For example, the phenyl-p-benzoquinonetest may be used to establish analgesic effectiveness. Thephenyl-p-benzoquinone induced writhing test in mice (H. Blumberg et al.,1965, Proc. Soc. Exp. Med. 118:763-766) hereby incorporated byreference; and known modifications thereof) is a standard procedurewhich may be used for detecting and comparing the analgesic activity ofdifferent classes of analgesic drugs with a good correlation with humananalgesic activity. Data for the mouse, as presented in an isobologram,can be translated to other species where the orally effective analgesicdose of the individual compounds are known or can be estimated. Themethod consists of reading the percent ED50 dose for each dose ratio onthe best fit regression analysis curve from the mouse isobologram,multiplying each component by its effective species dose, and thenforming the ratio of the amount of COX-2 inhibitor and opioid analgesic.This basic correlation for analgesic properties enables estimation ofthe range of human effectiveness (E. W. Pelikan, 1959, ThePharmacologist 1:73; hereby incorporated by reference).

[0064] Application of an equieffective dose substitution model and acurvilinear regression analysis utilizing all the data for theindividual compounds and various dose ratios for the combinationsestablishes the existence of unexpectedly enhanced analgesic activity ofcombinations of COX-2 inhibitor and opioid analgesic, i.e., theresulting activity is greater than the activity expected from the sum ofthe activities of the individual components.

[0065] The present invention encompasses immediate release dosage formsof an effective analgesic amount of a COX-2 inhibitor and opioidanalgesic combination. An immediate release dosage form may beformulated as a tablet or multiparticulate which may be encapsulated.Other immediate release dosage forms known in the art can be employed.

[0066] Compositions of the invention present the opportunity forobtaining relief from moderate to severe pain with or withoutinflammation. Due to the synergistic and/or additive effects provided bythe inventive combination of opioid analgesic and COX-2 inhibitor, itmay be possible to use reduced dosages of each of COX-2 inhibitor andopioid analgesic. By using lesser amounts of other or both drugs, theside effects associated with each may be reduced in number and degree.Moreover, the inventive combination avoids side effects to which somepatients are particularly sensitive.

[0067] The present invention encompasses a method of inhibiting COX-2and treating COX-2 mediated diseases comprising administering to apatient in need of such treatment a non-toxic therapeutically effectiveamount of the COX-2 inhibitor and opioid analgesic combination of thepresent invention. These diseases include moderate to severe painarising from many different etiologies, including but not limited tocancer pain and post-surgical pain, fever and inflammation of a varietyof conditions including rheumatic fever, symptoms associated withinfluenza or other viral infections, common cold, low back and neckpain, dysmenorrhea, headache, toothache, sprains and strains, myositis,neuralgia, synovitis, arthritis, including rheumatoid arthritis,degenerative joint diseases (osteoarthritis), gout and ankylosingspondylitis, bursitis, burns, and injuries. Further, the combination ofCOX-2 inhibitor and opioid analgesic is useful as an alternative toconventional non-steroidal anti-inflammatory drugs or combinations ofNSAID'S with other drugs particularly where such non-steroidalanti-inflammatory drugs may be contra-indicated such as in patients withpeptic ulcers, gastritis, regional enteritis, ulcerative colitis,diverticulitis or with a recurrent history of gastrointestinal lesions;GI bleeding, coagulation disorders including anemia such ashypoprothrombinemia, haemophilia or other bleeding problems; kidneydisease; those prior to surgery or taking anticoagulants.

[0068] The sustained release dosage forms of the present inventiongenerally achieve and maintain therapeutic levels substantially withoutsignificant increases in the intensity and/or degree of concurrent sideeffects, such as nausea, vomiting or drowsiness, which are oftenassociated with high blood levels of opioid analgesics. There is alsoevidence to suggest that the use of the present dosage forms leads to areduced risk of drug addiction.

[0069] The combination of COX-2 inhibitor and oral opioid analgesics maybe formulated to provide for an increased duration of analgesic actionallowing once-daily dosing. These formulations, at comparable dailydosages of conventional immediate release drug, are associated with alower incidence in severity of adverse drug reactions and can also beadministered at a lower daily dose than conventional oral medicationwhile maintaining pain control.

[0070] The combination of COX-2 inhibitor and an opioid analgesic can beemployed in admixtures with conventional excipients, i.e.,pharmaceutically acceptable organic or inorganic carrier substancessuitable for oral, parenteral, nasal, intravenous, subcutaneous,enteral, or any other suitable mode of administration, known to the art.Suitable pharmaceutically acceptable carriers include but are notlimited to water, salt solutions, alcohols, gum arabic, vegetable oils,benzyl alcohols, polyethylene glycols, gelate, carbohydrates such aslactose, amylose or starch, magnesium stearate talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure buffers, coloring, flavoring and/oraromatic substances and the like. They can also be combined wheredesired with other active agents, e.g., other analgesic agents. Forparenteral application, particularly suitable are oily or aqueoussolutions, as well as suspensions, emulsions, or implants, includingsuppositories. Ampoules are convenient unit dosages. For oralapplication, particularly suitable are tablets, dragees, liquids, drops,suppositories, or capsules, caplets and gelcaps. The compositionsintended for oral use may be prepared according to any method known inthe art and such compositions may contain one or more agents selectedfrom the group consisting of inert, non-toxic pharmaceuticallyexcipients which are suitable for the manufacture of tablets. Suchexcipients include, for example an inert diluent such as lactose;granulating and disintegrating agents such as cornstarch; binding agentssuch as starch; and lubricating agents such as magnesium stearate. Thetablets may be uncoated or they may be coated by known teclniques forelegance or to delay release of the active ingredients. Formulations fororal use may also be presented as hard gelatin capsules wherein theactive ingredient is mixed with an inert diluent.

[0071] Aqueous suspensions contain the above-identified combination ofdrugs and that mixture has one or more excipients suitable as suspendingagents, for example pharmaceutically acceptable synthetic gums such ashydroxypropylmethylcellulose or natural gums. Oily suspensions may beformulated by suspending the above-identified combination of drugs in avegetable oil or mineral oil. The oily suspensions may contain athickening agent such as beeswax or cetyl alcohol. A syrup, elixir, orthe like can be used wherein a sweetened vehicle is employed. Injectablesuspensions may also be prepared, in which case appropriate liquidcarriers, suspending agents and the like may be employed. It is alsopossible to freeze-dry the active compounds and use the obtainedlyophilized compounds, for example, for the preparation of products forinjection.

[0072] The method of treatment and pharmaceutical formulations of thepresent invention may further include one or more drugs in addition to aCOX-2 inhibitor and an opioid analgesic, which additional drug(s) may ormay not act synergistically therewith. Examples of such additional drugsinclude non-steroidal anti-inflammatory agents, including ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zido-metacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam orisoxicam, and the like. Other suitable additional drugs which may beincluded in the dosage forms of the present invention includeacetaminophen, aspirin, and other non-opioid analgesics.

CONTROLLED RELEASE DOSAGE FORMS

[0073] The COX-2 inhibitor and opioid analgesic combination can beformulated as a controlled or sustained release oral formulation in anysuitable tablet, coated tablet or multiparticulate formulation known tothose skilled in the art. The sustained release dosage form mayoptionally include a sustained released carrier which is incorporatedinto a matrix along with the opioid, or which is applied as a sustainedrelease coating.

[0074] The sustained release dosage form may include the opioidanalgesic in sustained release form and COX-2 inhibitor in sustainedrelease form or in immediate release form. The COX-2 inhibitor may beincorporated into the sustained release matrix along with the opioid;incorporated into the sustained release coating; incorporated as aseparated sustained release layer or immediate release layer; or may beincorporated as a powder, granulation, etc., in a gelatin capsule withthe substrates of the present invention. Alternatively, the sustainedrelease dosage form may have the COX-2 inhibitor in sustained releaseform and the opioid analgesic in sustained release form or immediaterelease form.

[0075] An oral dosage form according to the invention may be providedas, for example, granules, spheroids, beads, pellets (hereinaftercollectively referred to as “multiparticulates”) and/or particles. Anamount of the multiparticulates which is effective to provide thedesired dose of opioid over time may be placed in a capsule or may beincorporated in any other suitable oral solid form.

[0076] In one preferred embodiment of the present invention, thesustained release dosage form comprises such particles containing orcomprising the active ingredient, wherein the particles have diameterfrom about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about2 mm.

[0077] In certain embodiments, the particles comprise normal releasematrixes containing the opioid analgesic with or without the COX-2inhibitor. These particles are then coated with the sustained releasecarrier in embodiments where the COX-2 inhibitor is immediatelyreleased, the COX-2 inhibitor may be included in separate normal releasematrix particles, or may be co-administered in a different immediaterelease composition which is either enveloped within a gelatin capsuleor is administered separately. In other embodiments, the particlescomprise inert beads which are coated with the opioid analgesic with orwithout the COX-2 inhibitor. Thereafter, a coating comprising thesustained release carrier is applied onto the beads as an overcoat.

[0078] The particles are preferably film coated with a material thatpermits release of the opioid (or salt) and if desired, the COX-2inhibitor, at a sustained rate in an aqueous medium. The film coat ischosen so as to achieve, in combination with the other statedproperties, a desired in-vitro release rate. The sustained releasecoating formulations of the present invention should be capable ofproducing a strong, continuous film that is smooth and elegant, capableof supporting pigments and other coating additives, non-toxic, inert,and tack-free.

COATINGS

[0079] The dosage forms of the present invention may optionally becoated with one or more materials suitable for the regulation of releaseor for the protection of the formulation. In one embodiment, coatingsare provided to permit either pH-dependent or pH-independent release,e.g., when exposed to gastrointestinal fluid. A pH-dependent coatingserves to release the opioid in desired areas of the gastro-intestinal(GI) tract, e.g., the stomach or small intestine, such that anabsorption profile is provided which is capable of providing at leastabout twelve hour and preferably up to twenty-four hour analgesia to apatient. When a pH-independent coating is desired, the coating isdesigned to achieve optimal release regardless of pH-changes in theenvironmental fluid, e.g., the GI tract. It is also possible toformulate compositions which release a portion of the dose in onedesired area of the GI tract, e.g., the stomach, and release theremainder of the dose in another area of the GI tract, e.g., the smallintestine.

[0080] Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

[0081] In certain preferred embodiments, the substrate (e.g., tabletcore bead, matrix particle) containing the opioid analgesic (with orwithout the COX-2 inhibitor) is coated with a hydrophobic materialselected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii)mixtures thereof. The coating may be applied in the form of an organicor aqueous solution or dispersion. The coating may be applied to obtaina weight gain from about 2 to about 25% of the substrate in order toobtain a desired sustained release profile. Such formulations aredescribed, e.g., in detail in U.S. Pat. Nos. 5,273,760 and 5,286,493,assigned to the Assignee of the present invention and herebyincorporated by reference.

[0082] Other examples of sustained release formulations and coatingswhich may be used in accordance with the present invention includeAssignee's U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712, herebyincorporated by reference in their entirety.

[0083] Alkylcellulose Polymers

[0084] Cellulosic materials and polymers, including alkylcelluloses,provide hydrophobic materials well suited for coating the beadsaccording to the invention. Simply by way of example, one preferredalkylcellulosic polymer is ethylcellulose, although the artisan willappreciate that other cellulose and/or alkylcellulose polymers may bereadily employed, singly or in any combination, as all or part of ahydrophobic coating according to the invention.

[0085] One commercially-available aqueous dispersion of ethylcelluloseis Aquacoat® (FMC Corp., Philadelphia, Pa., U.S.A.). Aquacoat® isprepared by dissolving the ethylcellulose in a water-immiscible organicsolvent and then emulsifying the same in water in the presence of asurfactant and a stabilizer. After homogenization to generate submicrondroplets, the organic solvent is evaporated under vacuum to form apseudolatex. The plasticizer is not incorporated in the pseudolatexduring the manufacturing phase. Thus, prior to using the same as acoating, it is necessary to intimately mix the Aquacoat® with a suitableplasticizer prior to use.

[0086] Another aqueous dispersion of ethylcellulose is commerciallyavailable as Surelease® (Colorcon, Inc., West Point, Pa., U.S.A.). Thisproduct is prepared by incorporating plasticizer into the dispersionduring the manufacturing process. A hot melt of a polymer, plasticizer(dibutyl sebacate), and stabilizer (oleic acid) is prepared as ahomogeneous mixture, which is then diluted with an alkaline solution toobtain an aqueous dispersion which can be applied directly ontosubstrates.

[0087] Acrylic Polymers

[0088] In other preferred embodiments of the present invention, thehydrophobic material comprising the controlled release coating is apharmaceutically acceptable acrylic polymer, including but not limitedto acrylic acid and methacrylic acid copolymers, methyl methacrylatecopolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate,poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamidecopolymer, poly(methyl methacrylate), polymethacrylate, poly(methylmethacrylate) copolymer, polyacrylamide, aminoalkyl methacrylatecopolymer, poly(methacrylic acid anhydride), and glycidyl methacrylatecopolymers.

[0089] In certain preferred embodiments, the acrylic polymer iscomprised of one or more ammonio methacrytate copolymers. Ammoniomethacrylate copolymers are well known in the art, and are described inNF XVII as fully polymerized copolymers of acrylic and methacrylic acidesters with a low content of quaternary ammonium groups.

[0090] In order to obtain a desirable dissolution profile, it may benecessary to incorporate two or more ammonio methacrylate copolymershaving differing physical properties, such as different molar ratios ofthe quaternary ammonium groups to the neutral (meth)acrylic esters.

[0091] Certain methacrylic acid ester-type polymers are useful forpreparing pH-dependent coatings which may be used in accordance with thepresent invention. For example, there are a family of copolymerssynthesized from diethylaminoethyl methacrylate and other neutralmethacrylic esters, also known as methacrylic acid copolymer orpolymeric methacrylates, commercially available as Eudragit® from RöhmTech, Inc. There are several different types of Eudragit®. For example,Eudragit® E is an example of a methacrylic acid copolymer which swellsand dissolves in acidic media. Eudragit® L is a methacrylic acidcopolymer which does not swell at about pH<5.7 and is soluble at aboutpH>6. Eudragit® S does not swell at about pH<6.5 and is soluble at aboutpH>7. Eudragit® RL and Eudragit® RS are water swellable, and the amountof water absorbed by these polymers is pH-dependent, however, dosageforms coated with Eudragit® RL and RS are pH-independent.

[0092] In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

[0093] The Eudragit® RL/RS dispersions of the present invention may bemixed together in any desired ratio in order to ultimately obtain asustained release formulation having a desirable dissolution profile.Desirable sustained release formulations may be obtained, for instance,from a retardant coating derived from 100% Eudragit® RL, 50% Eudragit®RL and 50% Eudragit® RS, and 10% Eudragit® RL:Eudragit® 90% RS. Ofcourse, one skilled in the art will recognize that other acrylicpolymers may also be used, such as, for example, Eudragit® L.

[0094] Plasticizers

[0095] In embodiments of the present invention where the coatingcomprises an aqueous dispersion of a hydrophobic material, the inclusionof an effective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethylcellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent by weight of the film-former. Concentration of theplasticizer, however, can only be properly determined after carefulexperimentation with the particular coating solution and method ofapplication.

[0096] Examples of suitable plasticizers for ethylcellulose includewater insoluble plasticizers such as dibutyl sebacate, diethylphthalate, triethyl citrate, tributyl citrate, and triacetin, althoughit is possible that other water-insoluble plasticizers (such asacetylated monoglycerides, phthalate esters, castor oil, etc.) may beused. Triethyl citrate is an especially preferred plasticizer for theaqueous dispersions of ethyl cellulose of the present invention.

[0097] Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

[0098] It has further been found that the addition of a small amount oftalc reduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

PROCESSES FOR PREPARING COATED BEADS

[0099] When the aqueous dispersion of hydrophobic material is used tocoat inert pharmaceutical beads such as nu pariel 18/20 beads, aplurality of the resultant stabilized solid controlled release beads maythereafter be placed in a gelatin capsule in an amount sufficient toprovide an effective controlled release dose when ingested and contactedby an environmental fluid, e.g., gastric fluid or dissolution media.

[0100] The stabilized controlled release bead formulations of thepresent invention slowly release the therapeutically active agent, e.g.,when ingested and exposed to gastric fluids, and then to intestinalfluids. The controlled release profile of the formulations of theinvention can be altered, for example, by varying the amount ofovercoating with the aqueous dispersion of hydrophobic material,altering the manner in which the plasticizer is added to the aqueousdispersion of hydrophobic material, by varying the amount of plasticizerrelative to hydrophobic material, by the inclusion of additionalingredients or excipients, by altering the method of manufacture, etc.The dissolution profile of the ultimate product may also be modified,for example, by increasing or decreasing the thickness of the retardantcoating.

[0101] Spheroids or beads coated with a therapeutically active agent areprepared, e.g., by dissolving the therapeutically active agent in waterand then spraying the solution onto a substrate, for example, nu pariel18/20 beads, using a Wuster insert. Optionally, additional ingredientsare also added prior to coating the beads in order to assist the bindingof the opioid to the beads, and/or to color the solution, etc. Forexample, a product which includes hydroxypropylmethylcellulose, etc.with or without colorant (e.g., Opadry®, commercially available fromColorcon, Inc.) may be added to the solution and the solution mixed(e.g., for about 1 hour) prior to application of the same onto thebeads. The resultant coated substrate, in this example beads, may thenbe optionally overcoated with a barrier agent, to separate thetherapeutically active agent from the hydrophobic controlled releasecoating. An example of a suitable barrier agent is one which compriseshydroxypropylmethylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

[0102] The beads may then be overcoated with an aqueous dispersion ofthe hydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

[0103] The coating solutions of the present invention preferablycontain, in addition to the film-former, plasticizer, and solvent system(i.e., water), a colorant to provide elegance and product distinction.Color may be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

[0104] The plasticized aqueous dispersion of hydrophobic material may beapplied onto the substrate comprising the therapeutically active agentby spraying using any suitable spray equipment known in the art. In apreferred method, a Wurster fluidized-bed system is used in which an airjet, injected from underneath, fluidizes the core material and effectsdrying while the acrylic polymer coating is sprayed on. A sufficientamount of the aqueous dispersion of hydrophobic material to obtain apredetermined controlled release of said therapeutically active agentwhen said coated substrate is exposed to aqueous solutions, e.g. gastricfluid, is preferably applied, taking into account the physicalcharacteristics of the therapeutically active agent, the manner ofincorporation of the plasticizer, etc. After coating with thehydrophobic material, a further overcoat of a film-former, such asOpadry®, is optionally applied to the beads. This overcoat is provided,if at all, in order to substantially reduce agglomeration of the beads.

[0105] The release of the therapeutically active agent from thecontrolled release formulation of the present invention can be furtherinfluenced, i.e., adjusted to a desired rate, by the addition of one ormore release-modifying agents, or by providing one or more passagewaysthrough the coating. The ratio of hydrophobic material to water solublematerial is determined by, among other factors, the release raterequired and the solubility characteristics of the materials selected.

[0106] The release-modifying agents which function as pore-formers maybe organic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in the environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

[0107] The sustained release coatings of the present invention can alsoinclude erosion-promoting agents such as starch and gums.

[0108] The sustained release coatings of the present invention can alsoinclude materials useful for making microporous lamina in theenvironment of use, such as polycarbonates comprised of linearpolyesters of carbonic acid in which carbonate groups reoccur in thepolymer chain.

[0109] The release-modifying agent may also comprise a semi-permeablepolymer.

[0110] In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

[0111] The sustained release coatings of the present invention may alsoinclude an exit means comprising at least one passageway, orifice, orthe like. The passageway may be formed by such methods as thosedisclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and4,088,864 (all of which are hereby incorporated by reference). Thepassageway can have any shape such as round, triangular, square,elliptical, irregular, etc.

[0112] Matrix Bead Formulations

[0113] In other embodiments of the present invention, the controlledrelease formulation is achieved via a matrix having a controlled releasecoating as set forth above. The present invention may also utilize acontrolled release matrix that affords in-vitro dissolution rates of theopioid within the preferred ranges and that releases the opioid in apH-dependent or pH-independent manner. The materials suitable forinclusion in a controlled release matrix will depend on the method usedto form the matrix.

[0114] For example, a matrix in addition to the opioid analgesic and(optionally) COX-2 may include:

[0115] Hydrophilic and/or hydrophobic materials, such as gums, celluloseethers, acrylic resins, protein derived materials; the list is not meantto be exclusive, and any pharmaceutically acceptable hydrophobicmaterial or hydrophilic material which is capable of impartingcontrolled release of the active agent and which melts (or softens tothe extent necessary to be extruded) may be used in accordance with thepresent invention.

[0116] Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substitutedor unsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes,and stearyl alcohol; and polyalkylene glycols.

[0117] Of these polymers, acrylic polymers, especially Eudragit®RSPO—the cellulose ethers, especially hydroxyalkylcelluloses andcarboxyalkylcelluloses, are preferred. The oral dosage form may containbetween 1% and 80% (by weight) of at least one hydrophilic orhydrophobic material.

[0118] When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25 and 90 C. Of the long chainhydrocarbon materials, fatty (aliphatic) alcohols are preferred. Theoral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.

[0119] Preferably, the oral dosage form contains Up to 60% (by weight)of at least one polyalkylene glycol.

[0120] The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cynaoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing.

[0121] Preferred hydrophobic materials are water-insoluble with more orless pronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 30 to about 200 C., preferably from about 45 to about 90 C.Specifically, the hydrophobic material may comprise natural or syntheticwaxes , fatty alcohols (such as lauryl, myristyl, stearyl, cetyl orpreferably cetostearyl alcohol), fatty acids, including but not limitedto fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicaid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include, for example, beeswax,glycowax, castor wax and carnauba wax. For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about30 to about 100 C.

[0122] Suitable hydrophobic materials which may be used in accordancewith the present invention include digestible, long chain (C₈₋C₅₀,especially C₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such asfatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and natural and synthetic waxes. Hydrocarbons having amelting point of between 25 and 90 C are preferred. Of the long chainhydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

[0123] Preferably, a combination of two or more hydrophobic materialsare included in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably selected from natural andsynthetic waxes, fatty acids, fatty alcohols, and mixtures of the same.Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is not meant to be exclusive.

[0124] One particular suitable matrix comprises at least one watersoluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol. The at least one hydroxyalkyl cellulose is preferably a hydroxy(C₁ to C₆) alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate ofopioid release required. The at least one aliphatic alcohol may be, forexample, lauryl alcohol, myristyl alcohol or stearyl alcohol. Inparticularly preferred embodiments of the present oral dosage form,however, the at least one aliphatic alcohol is cetyl alcohol orcetostearyl alcohol. The amount of the at least one aliphatic alcohol inthe present oral dosage form will be determined, as above, by theprecise rate of opioid release required. It will also depend on whetherat least one polyalkylene glycol is present in or absent from the oraldosage form. In the absence of at least one polyalkylene glycol, theoral dosage form preferably contains between 20% and 50% (by wt) of theat least one aliphatic alcohol. When at least one polyalkylene glycol ispresent in the oral dosage form, then the combined weight of the atleast one aliphatic alcohol and the at least one polyalkylene glycolpreferably constitutes between 20% and 50% (by wt) of the total dosage.

[0125] In one embodiment, the ratio of, e.g., the at least onehydroxyalkyl cellulose or acrylic resin to the at least one aliphaticalcohol/ polyalkylene glycol determines, to a considerable extent, therelease rate of the opioid from the formulation. A ratio of the at leastone hydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

[0126] The at least one polyalkylene glycol may be, for example,polypropylene glycol or, which is preferred, polyethylene glycol. Thenumber average molecular weight of the at least one polyalkylene glycolis preferred between 1,000 and 15,000 especially between 1,500 and12,000.

[0127] Another suitable controlled release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

[0128] In another preferred embodiment, the matrix includes apharmaceutically acceptable combination of at least two hydrophobicmaterials.

[0129] In addition to the above ingredients, a controlled release matrixmay also contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

PROCESSES FOR PREPARING MATRIX-BASED BEADS

[0130] In order to facilitate the preparation of a solid, controlledrelease, oral dosage form according to this invention, any method ofpreparing a matrix formulation known to those skilled in the art may beused. For example incorporation in the matrix may be effected, forexample, by (a) forming granules comprising at least one water solublehydroxyalkyl cellulose and opioid or an opioid salt; (b) mixing thehydroxyalkyl cellulose containing granules with at least one C₁₂-C₃₆aliphatic alcohol; and (c) optionally, compressing and shaping thegranules. Preferably, the granules are formed by wet granulating thehydroxyalkyl cellulose/opioid with water. In a particularly preferredembodiment of this process, the amount of water added during the wetgranulation step is preferably between 1.5 and 5 times, especiallybetween 1.75 and 3.5 times, the dry weight of the opioid.

[0131] In yet other alternative embodiments, a spheronizing agent,together with the active ingredient can be spheronized to formspheroids. Microcrystalline cellulose is preferred. A suitablemicrocrystalline cellulose is, for example, the material sold as AvicelPH 101 (Trade Mark, FMC Corporation). In such embodiments, in additionto the active ingredient and spheronizing agent, the spheroids may alsocontain a binder. Suitable binders, such as low viscosity, water solublepolymers, will be well known to those skilled in the pharmaceutical art.However, water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

[0132] Melt Extrusion Matrix

[0133] Sustained release matrices can also be prepared viamelt-granulation or melt-extrusion techniques. Generally,melt-granulation techniques involve melting a normally solid hydrophobicmaterial, e.g. a wax, and incorporating a powdered drug therein. Toobtain a sustained release dosage form, it may be necessary toincorporate an additional hydrophobic substance, e.g. ethylcellulose ora water-insoluble acrylic polymer, into the molten wax hydrophobicmaterial. Examples of sustained release formulations prepared viamelt-granulation techniques are found in U.S. Pat. No. 4,861,598,assigned to the Assignee of the present invention and herebyincorporated by reference in its entirety.

[0134] The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

[0135] In addition to the above ingredients, a sustained release matrixmay also contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation.

[0136] In addition to the above ingredients, a sustained release matrixincorporating melt-extruded multiparticulates may also contain suitablequantities of other materials, e.g. dituents, lubricants, binders,granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% byweight of the particulate if desired.

[0137] Specific examples of pharmaceutically acceptable carriers andexcipients that may be used to formulate oral dosage forms are describedin the Handbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference herein.

[0138] Melt Extrusion Multiparticulates

[0139] The preparation of a suitable melt-extruded matrix according tothe present invention may, for example, include the steps of blendingthe opioid analgesic, together with at least one hydrophobic materialand preferably the additional hydrophobic material to obtain ahomogeneous mixture. The homogeneous mixture is then heated to atemperature sufficient to at least soften the mixture sufficiently toextrude the same. The resulting homogeneous mixture is then extruded toform strands. The extrudate is preferably cooled and cut intomultiparticulates by any means known in the art. The strands are cooledand cut into multiparticulates. The multiparticulates are then dividedinto unit doses. The extrudate preferably has a diameter of from about0.1 to about 5 mm and provides sustained release of the therapeuticallyactive agent for a time period of from about 8 to about 24 hours.

[0140] An optional process for preparing the melt extrusions of thepresent invention includes directly metering into an extruder ahydrophobic material, a therapeutically active agent, and an optionalbinder; heating the homogenous mixture; extruding the homogenous mixtureto thereby form strands; cooling the strands containing the homogeneousmixture; cutting the strands into particles having a size from about 0.1mm to about 12 mm; and dividing said particles into unit doses. In thisaspect of the invention, a relatively continuous manufacturing procedureis realized.

[0141] The diameter of the extruder aperture or exit port can also beadjusted to vary the thickness of the extruded strands. Furthermore, theexit part of the extruder need not be round; it can be oblong,rectangular, etc. The exiting strands can be reduced to particles usinga hot wire cutter, guillotine, etc.

[0142] The melt extruded multiparticulate system can be, for example, inthe form of granules, spheroids or pellets depending upon the extruderexit orifice. For purposes of the present invention, the terms“melt-extruded multiparticulate(s)” and “melt-extruded multiparticulatesystem(s)” and “melt-extruded particles” shall refer to a plurality ofunits, preferably within a range of similar size and/or shape andcontaining one or more active agents and one or more excipients,preferably including a hydrophobic material as described herein. In thisregard, the melt-extruded multiparticulates will be of a range of fromabout 0.1 to about 12 mm in length and have a diameter of from about 0.1to about 5 mm. In addition, it is to be understood that themelt-extruded multiparticulates can be any geometrical shape within thissize range. Alternatively, the extrudate may simply be cut into desiredlengths and divided into unit doses of the therapeutically active agentwithout the need of a spheronization step.

[0143] In one preferred embodiment, oral dosage forms are prepared toinclude an effective amount of melt-extruded multiparticulates within acapsule. For example, a plurality of the melt-extruded multipaiticulatesmay be placed in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

[0144] In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980),incorporated by reference herein.

[0145] In yet another preferred embodiment, the extrudate can be shapedinto tablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et.al.), described in additional detail above and hereby incorporated byreference.

[0146] Optionally, the sustained release melt-extruded multiparticulatesystems or tablets can be coated, or the gelatin capsule can be furthercoated, with a sustained release coating such as the sustained releasecoatings described above. Such coatings preferably include a sufficientamount of hydrophobic material to obtain a weight gain level from about2 to about 30 percent, although the overcoat may be greater dependingupon the physical properties of the particular opioid analgesic compoundutilized and the desired release rate, among other things.

[0147] The melt-extruded unit dosage forms of the present invention mayfurther include combinations of melt-extruded multiparticulatescontaining one or more of the therapeutically active agents disclosedabove before being encapsulated. Furthermore, the unit dosage forms canalso include an amount of an immediate release therapeutically activeagent for prompt therapeutic effect. The immediate releasetherapeutically active agent may be incorporated, e.g., as separatepellets within a gelatin capsule, or may be coated on the surface of themultiparticulates after preparation of the dosage forms (e.g.,controlled release coating or matrix-based). The unit dosage forms ofthe present invention may also contain a combination of controlledrelease beads and matrix multiparticulates to achieve a desired effect.

[0148] The sustained release formulations of the present inventionpreferably slowly release the therapeutically active agent, e.g., wheningested and exposed to gastric fluids, and then to intestinal fluids.The sustained release profile of the melt-extruded formulations of theinvention can be altered, for example, by varying the amount ofretardant, i.e., hydrophobic material, by varying the amount ofplasticizer relative to hydrophobic material, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture, etc.

[0149] In other embodiments of the invention, the melt extruded materialis prepared without the inclusion of the therapeutically active agent,which is added thereafter to the extrudate. Such formulations typicallywill have the therapeutically active agent blended together with theextruded matrix material, and then the mixture would be tableted inorder to provide a slow release formulation. Such formulations may beadvantageous, for example, when the therapeutically active agentincluded in the formulation is sensitive to temperatures needed forsoftening the hydrophobic material and/or the retardant material.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0150] The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

EXAMPLES 1-2 Evaluation of Combination of Morphine and Nabumetone(Example 1) and Morphine and Meloxicam (Example 2)

[0151] In Examples 1-2, COX-2 inhibitor-opiate synergy were examined byexamining nabumetone (Example 1) and meloxicam (Example 2) in aPhenylquinone (PPQ) stretching (writhing) test.

[0152] Nabumetone is not intrinsically COX-2-selective, but is evaluatedhere because its use is associated with extremely low ulcerogenesis.Nabumetone is a prodrug, giving rise to the actual COX-2 inhibitor,6-methoxy-2-naphthylacetic acid (6-MNA). (see Table 1). The lowulcerogenic potential of nabumetone may be due to the pH-dependentformation of 6-MNA. This does not occur at low pH values, such as thosefound in the gastric mucosa. Thus, COX-2 selectivity appears to befunctional. In clinical trials, nabumetone has been found to be quiteefficacious, with extremely little ulcerogenesis. In a trial in patientswith osteoartlritis, nabumetone was compared to diclofenac. It was foundto be as efficacious as diclofenac (it is extremely impotent, requiring1500 mg daily), however, none of the 382 patients treated withnabumetone experienced gastrointestinal toxicity (S. H. Roth et al, J.Rheumatol. 21:1118, 1994). In a report of 1-year follow-up of patientstreated with nabumetone, the incidence of ulcers was only 0.5% (PDR1995, p. 2396).

[0153] Methods: Isobolographic analysis of drug interaction wasperformed in male ICR mice. At time=0, meloxicam or nabumetone orvehicle was administered p.o. At time (T)=9 minutes, morphine or vehiclewas administered p.o. At T=29 minutes, PPQ (phenyl-p-benzylquinone), 2mg/kg, was injected i.p. At T=36 minutes, the number of abdominalstretches was counted for each mouse for 1 minute. At T=40 minutes,stretches were again counted for 1 minute. There were 6-8 mice per dose.

[0154] The concentrations of morphine used for its dose-response were0.5, 1, 2, and 5 mg/kg. The concentrations of nabumetone used for itsdose-response were 20, 50, 100, and 300 mg/kg. The concentrations ofmeloxicam used for its dose-response were 1, 3, 10, and 50 mg/kg.

[0155] The % inhibition of PPQ stretching (writhing) test was calculatedas follows:

=1−{[total # stretches at two countings with drug]/[total # stretches attwo countings with vehicle]}×100

[0156] ED50 (the dose of drug that caused an inhibition of 50%) wasdetermined by nonlinear regression. When combinations of morphine andmeloxicam or nabumetone were administered, the ratio was always set at1:10 or 1:1000, respectively. For the combination studies, the followingwere used: morphine/nabumetone were 0.036/36, 0.072/72, 0.1/100, and0.144/144 mg/kg, morphine/meloxicam were 0.18/1.8, 0.36/3.6, 0.72/7.2,and 1.44/14.4 mg/kg. The ED50 for each drug in the combination wasdetermined by simple calculation of the amount of each in thecombination at the ED50 combination dose. The ED50 results for Example 1(nabumetone) versus morphine are set forth below:

[0157] nabumetone: morphine ED50=1.86 mg/kg po (confidence interval1.39-2.5)

[0158] nabumetone ED50 92.1 mg/kg po (slight extrapolation)

[0159] with combination dose-response using morphine:nabumetone 1:1000

[0160] ED50 morphine=0.06 (confidence interval is 0.02 to 0.17)

[0161] ED50 nabumetone=64.5.

[0162] As can be seen from the ED50 results, nabumetone significantlyincreased the potency of morphine. While morphine did not affect thepotency of nabumetone in a statistically significant manner, it didshift the ED50 results to an extent which suggests that increasing theratio of nabumetone to morphine may result in two-way synergy. In viewof this result, the combination of a much more potent COX-2 inhibitorsuch as celecoxib will provide statistically significant two-waysynergy. In such a combination, the opioid will be seen to significantlypotentiate the analgesic effecticacy of celecoxib.

[0163] The ED50 results for Example 2 (meloxicam) are set forth below:

[0164] meloxicam: morphine ED50=1.86 mg/kg po

[0165] meloxicam ED50 15.2 mg/kg po (slight extrapolation)

[0166] with combination dose-response using morphine:meloxicam 1:10

[0167] ED50 morphine=0.62

[0168] ED50 meloxicam=6.22.

[0169] As can be seen from the ED50 results, meloxicam significantlyincreased the potency of morphine, whereas morphine did not affect thepotency of meloxicam. Morphine did however, allow meloxicam to reachbetter efficacy—72% vs 45% inhibition.

[0170] The data obtained from Examples 1-2 are further represented inFIG. 1, which is a graph depicting the percent inhibition (ED50) plottedagainst the dose (mg/kg). FIG. 1 includes plots of dose-response datafor nabumetone, meloxicam and morphine alone, and for combinations ofnabumetone+morphine and meloxicam+morphine. As can be seen from theresults set forth in FIG. 1, morphine did not shift the dose-responsefor nabumetone or meloxicam. However, nabumetone and meloxicam bothshifted the dose-response for morphine (indicated by the arrows).

[0171] The interaction of morphine and flusolide can be demonstrated viaan isobologram. (See, e.g., S. Loewe, Pharm. Rev., 9;237 (1957))regarding the preparation and basis of an isobologram; herebyincorporated by reference).

[0172]FIG. 2 is an isobologram for nabumetone in interaction withmorphine (included are 95% confidence intervals) . The diagonal linejoining the ED₅₀ values of the two drugs given separately represents thesimple additivity of effects at different component ratios. ED₅₀ valuesfalling under the curve (between the line and the origin) indicatesuperadditivity. As can be seen from FIG. 2, the combination ofnabumetone and morphine exhibited synergism supporting the ratios of thecombinations of these drugs set forth in Table II.

[0173]FIG. 3 is an isobologram for meloxicam in interaction withmorphine (included are 95% confidence intervals). As can be seen fromFIG. 3, the combination of nabumetone and morphine exhibited synergismsupporting the ratios of the combinations of these drugs set forth inTable II.

[0174] It is known to the art that data for the mouse, as presented inan isobologram, can be translated to other species where the orallyeffective analgesic dose of the individual compounds are known or can beestimated. Therefore, one of ordinary skill in the art will appreciatethat this basic correlation for analgesic properties enables estimationof the range of human effectiveness.

[0175] Conclusion

[0176] While the invention has been described and illustrated withreference to certain preferred embodiments thereof, those skilled in theart will appreciate that obvious modifications can be made hereinwithout departing from the spirit and scope of the invention. Forexample, effective dosages and the specific pharmacological responsesmay vary depending upon the ratios of the particular opioid toparticular COX-2 inhibitor used, as well as the formulation and mode ofadministration. Such variations are contemplated to be within the scopeof the appended claims.

What is claimed is:
 30. A pharmaceutical composition comprising ananalgesic combination consisting essentially of T-614 and oxycodone. 31.The pharmaceutical composition according to claim 30, wherein theoxycodone would be sub-therapeutic if administered without the T-614.32. The pharmaceutical composition according to claim 30, wherein theoxycodone and T-614 are administered orally, via implant, parenterally,sublingually, rectally, topically, or via inhalation.
 33. Thepharmaceutical composition according to claim 30, which is selected fromthe group consisting of a tablet; a multiparticulate formulation fororal administration; a solution, a suspension or elixir for oraladministration; an injectable formulation; an implantable device; atopical preparation; a suppository; a buccal tablet; and an inhalationformulation.
 34. The pharmaceutical composition according to claim 30,which is a solid oral dosage form selected from the group consisting ofa tablet and a capsule.
 35. The pharmaceutical composition according toclaim 30, wherein the ratio of oxycodone to T-614 is from about 0.0001:1 to about 1:1.
 36. The pharmaceutical composition according toclaim 30, wherein the T-614 synergistically potentiates the effect ofthe oxycodone but the oxycodone does not synergistically potentiate theeffect of the T-614.
 37. The pharmaceutical composition according toclaim 34, wherein the oral solid dosage form includes a sustainedrelease carrier which causes the sustained release of the T-614, theoxycodone, or both the oxycodone and the T-614 when the dosage formcontacts gastrointestinal fluid.
 38. A method of effectively treatingpain in humans or other mammals, comprising administering to a patientan analgesic combination consisting essentially of T-614 and oxycodonesuch that the dosing interval of the T-614 overlaps with the dosinginterval of the oxycodone.
 39. The method of claim 38, wherein the T-614and the oxycodone are administered orally.
 40. The method of claim 38,wherein the T-614 and the oxycodone are administered in a single oraldosage form.
 41. The method of claim 38, wherein the oxycodone would besub-therapeutic if administered without the T-614.
 42. The method ofclaim 38, wherein the T-614 is administered before, simultaneously with,or after administration of the oxycodone, such that the dosing intervalof the T-614 overlaps with the dosing interval of the oxycodone.
 43. Amethod of reducing the oxycodone required to treat a patient affectedwith pain, comprising co-administering said oxycodone with said T-614 toaugment the analgesia attributable to said oxycodone during at least aportion of the dosage interval of said oxycodone.
 44. A method ofreducing the amount of T-614 required to treat a patient affected withpain comprising co-administering said T-614 with an effective amount ofoxycodone, to augment the analgesia attributable to said T-614 during atleast a portion of the dosage interval of said T-614.
 45. Thepharmaceutical composition according to claim 1, wherein the oxycodoneis present in an amount from about 2.5 mg to about 800 mg.
 46. Themethod of claim 38, wherein the oxycodone is present in an amount fromabout 2.5 mg to about 800 mg.
 47. The method of claim 38, wherein theratio of oxycodone to T-614 is from about 0.0001:1 to about 1:1.